The rheological behavior of erythrocytes is an important determinant of microcirculatory blood flow. Although the crisis of sickle erythrocytes (SS cells) is highly dependent on the oxygen saturation level, little quantitative analysis has been done to determine the influence of cell heterogeneity on cellular deformability. It is therefore necessary to determine the role of sickle hemoglobin (Hb S) concentration on, and correlate SS cell rheology to, the effect of increased cellular hemoglobin concentration upon deoxygenation. Some of these concerns were quantitated in the course of this investigation, using a simple mathematical model of whole cell deformability in narrow vessels that combines previously published data of other investigators. During Hb S polymerization, the intracellular elasticity (or static rigidity) and viscosity (or dynamic rigidity) are functions of both oxygen saturation and Hb S concentration. The transition from cell membrane to internal polymer dominance of deformability depends on critical oxygen levels, with widely distributed Hb S concentration, at which sickling takes place. Thus, the variability of intracellular Hb S concentration is a characteristic feature of SS erythrocytes, and an important factor for the severity of the disease.